The rapid development of the artificial pancreas in the last few years had benefit from employing mathematical modeling and computer simulation. As a matter of fact, such in-silico testing provided direction for clinical studies, out-ruling ineffective control scenarios in a cost-effective manner [1-4]. In 2008, the present Applicant introduced a computer simulator of type 1 diabetes (T1DM) based on a meal simulation model of glucose-insulin system [5-7]. This simulator was equipped with 100 in-silico adults, 100 adolescents, and 100 children, and was accepted by the FDA as a substitute for preclinical trials of certain insulin treatments, including closed-loop algorithms [8].
The FDA Accepted Simulator
The Model
The model incorporated into the T1DM simulator, which describes the glucose-insulin control system during a meal, is described in detail in [5-7]. Briefly, the model puts in relation plasma concentrations, i.e., glucose G and insulin I, with glucose fluxes, i.e. endogenous glucose production (EGP), glucose rate of appearance (Ra), glucose utilization by the tissues (U), renal extraction (E), and insulin fluxes, i.e., rate of insulin appearance from the subcutaneous tissues (SC) and insulin degradation (D). The glucose subsystem consists of a two-compartment model of glucose kinetics: insulin-independent utilization occurs in first compartment, representing plasma and rapidly equilibrating tissues, while insulin-dependent utilization occurs in the second compartment, representing peripheral slowly equilibrating tissues. The insulin subsystem is also described with two compartments, representing liver and plasma, respectively. Subcutaneous insulin kinetics is represented by a subcutaneous insulin infusion module. Endogenous glucose production is assumed to be linearly dependent on plasma glucose concentration, portal insulin concentration and a delayed insulin signal. Glucose rate of appearance is described with a model of glucose transit through the stomach and intestine, with the stomach represented by two compartments, while a single compartment is used to describe the gut; the rate constant of gastric emptying is a nonlinear function of the amount of glucose in the stomach. Glucose utilization during a meal is made up of two compartments. The insulin-independent utilization by the brain and the erythrocytes takes place in the first compartment and is constant. The insulin-dependent utilization takes place in a remote compartment and depends nonlinearly from glucose in the tissues.
The Population of Type 1 Diabetic Virtual Subjects
The type 1 diabetes simulator is equipped with 100 virtual adults, 100 adolescents and 100 children. These populations of type 1 diabetic virtual subjects have been generated by randomly extracting different realizations of the parameter vector from appropriate joint parameter distributions. The initial (2007) parameters' joint distributions in T1DM were derived (after appropriate adjustment) from the available set in the adult healthy state. In particular, the inter-subject variability was assumed to be the same (same covariance matrix), but certain clinically-relevant modifications were introduced in the average parameter vector, for instance basal endogenous glucose production is higher in type 1 diabetic compared to normal subject. Similarly, parameter distribution in different type 1 diabetic populations, such as children and adolescents, have been obtained from that of type 1 diabetic adults by introducing certain clinically-relevant modifications in the average parameter vector, for instance insulin sensitivity is higher in children and lower in adolescents compared to adults [10].
As reported in [10], the validity of the computer simulation environment was tested on independent data. Several experiments aiming to assess its capability to reflect the variety of clinical situations as close as possible were conducted. For instance we reproduced the distribution of insulin correction factors in the T1DM population of children and adults; we reproduced glucose traces in children with T1DM observed in clinical trials performed by the DirectNet consortium and glucose traces of induced moderate hypoglycemia observed in adults in clinical trials at the University of Virginia, which guarantees comprehensive evaluation of control algorithms during hypoglycemia.
Despite the good agreement between simulation and real data, the FDA accepted simulator was never validated against specific meal test data performed in type 1 diabetes. Now that these data have finally become available [1-3], the clinical validity of the simulator can be assessed against a real T1DM population observed in clinical trials simulating normal life conditions, i.e. including a meal perturbation.
In particular, recent results show that the FDA accepted simulator performs well in eu- and hyper-glycemic zones, but it fails in some occasions in describing hypoglycemic events [11], as shown in FIG. 1. Thus, there exists a need in the art to address this failure.